Due to significant species-specific differences in liver pathways, in vitro models of the human liver play an important role in drug development and mechanistic investigations. Isolated primary human hepatocytes (PHHs) are ideal for constructing such models because they can maintain high levels of key liver functions for several weeks in vitro under specific culture conditions. However, PHHs are a severely limited resource given shortages in donor livers, and their quality for in vitro use can vary considerably across different cell lots.
Human stem cell-derived liver models, capable of assessing the hepatotoxicity of novel drugs prior to clinical implementation, have the potential to significantly reduce development costs, prevent undue morbidity, and advance personalized medicine. Hepatocyte-like cells have been produced from human induced pluripotent stem cells (iHeps) through the sequential delivery of growth factors, mirroring hepatic development. Current research indicates however that iHeps remain more fetal-like in phenotype, which substantially limits their use in toxicology screening.
Robust culture systems that can aid in discovering and screening novel drugs are needed. Such systems should exhibit: reproducible compatibility with banked cryopreserved human cells; in vivo-like and long-term (weeks) maintenance of mature hepatocyte phenotype and function; and require minimal (<10 mg) drug quantities to demonstrate a response, given limitations on manufacturing scale-up of new drug candidates.